Inactivation of the PtdIns(4)P phosphatase Sac1 at the Golgi by H2O2 produced via Ca2+-dependent Duox in EGF-stimulated cells

Sujin Park, Jung Mi Lim, Seon Hwa Park, Suree Kim, Sukyeong Heo, Tamas Balla, Woojin Jeong, Sue Goo Rhee, Dongmin Kang

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


Binding of epidermal growth factor (EGF) to its cell surface receptor induces production of H2O2, which serves as an intracellular messenger. We have shown that exogenous H2O2 reversibly inactivates the phosphatidylinositol 4-phosphate [PtdIns(4)P] phosphatase Sac1 (suppressor of actin 1) at the Golgi complex of mammalian cells by oxidizing its catalytic cysteine residue and thereby increases both the amount of Golgi PtdIns(4)P and the rate of protein secretion. Here we investigated the effects of EGF on Sac1 oxidation and PtdIns(4)P abundance at the Golgi in A431 cells. EGF induced a transient increase in Golgi PtdIns(4)P as well as a transient oxidation of Sac1 in a manner dependent on elevation of the intracellular Ca2+ concentration and on H2O2. Oxidation of Sac1 occurred at the Golgi, as revealed with the use of the Golgi-confined Sac1-K2A mutant. Knockdown of Duox enzymes implicated these Ca2+-dependent members of the NADPH oxidase family as the major source of H2O2 for Sac1 oxidation. Expression of a Golgi-targeted H2O2 probe revealed transient EGF-induced H2O2 production at this organelle. Our findings have thus uncovered a previously unrecognized EGF signaling pathway that links intracellular Ca2+ mobilization to events at the Golgi including Duox activation, H2O2 production, Sac1 oxidation, and PtdIns(4)P accumulation.

Original languageEnglish
Pages (from-to)40-49
Number of pages10
JournalFree Radical Biology and Medicine
StatePublished - 1 Feb 2019


  • Cysteine oxidation
  • Epidermal growth factor (EGF)
  • Golgi complex
  • Hydrogen peroxide
  • NADPH oxidase
  • Phosphatidylinositol 4-phosphate
  • Protein tyrosine phosphatase
  • Sac1


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